Alzheimer's disease (AD), the most prevalent cause of dementia, affects over 4.0 million individuals in the USA alone. Characteristic and diagnostic features of AD brains include degeneration of neurons, the accumulation of amyloid in neuritic (senile) plaques and perivascular regions, and the presence of neurofibrillary tangles. A major component of senile plaques is a 4 kD protein referred to as beta/A4. Beta/A4 is derived from one or more forms of a larger amyloid precursor protein (APP) which is constitutively expressed in brain. Although beta/A4 deposition is an early event in the pathogenesis of AD, the role that beta/A4 has in the neurodegenerative process is unknown, as are the normal function of APP and the mechanism by which beta/A4 is derived from APP. The long-term goals of this proposal are to determine the function of APP in normal brain and the mechanisms by which beta/A4 is derived from APP. Elucidating the cellular and subcellular distribution of APP and beta/A4 in normal brain and AD brain are essential for obtaining these goals. In vitro studies indicate that the APP extracellular domain is cleaved shortly after APP is inserted into plasma membranes. Specific Aim 1 of this proposal will test the hypothesis that APP is abundantly expressed in fetal mammalian brain, where it forms a matrix for the histotypic organization of neurons and neurites. Extracellular and cytoplasmic APP epitopes will be co-localized in tissue sections of fetal brain. Preliminary studies detect abundant APP in fetal brain and support this hypothesis. Specific Aim 2 will localize APP in light and electron micrographs of mammalian brain during postnatal development and ageing. It is predicted that little APP is expressed in normal postnatal brain. As ageing occurs, however, APP expression is upregulated to provide a matrix for neurite extension and neuropil rearrangement that accompanies neuronal death or atrophy. Studies in Specific Aim 3 will correlate the distribution of APP epitopes and beta/A4 in the CNS of individuals with Alzheimer's disease at the light and electron microscopic level. These studies will help elucidate the source of beta/A4 and the mechanisms involved in APP processing in AD brains. Collectively, the studies outlined in this proposal will provide valuable insights into the potential function of APP and the pathogenesis of amyloid formation.